Venezuelan equine encephalitis virus (VEEV) causes rapid, catastrophic swelling of
the brain and spinal cord, leading to severe neurological symptoms
and - in many cases - sudden death in animals. It is an unforgiving killer
of horses, donkeys and zebras, resulting in mortality as high as 80% of infected animals.
The virus can also infect humans, with
similar results. The United States and Soviet Union both weaponized VEEV during
the Cold War, prompting the Centers for Disease Control and the
National Institutes of Health to classify VEEV as a category B pathogen.
‘A far less deadly mutant version of the Venezuelan equine encephalitis virus (VEEV) has been discovered by scientists. This could enable the development of a vaccine and other drugs to combat VEEV.’
A research team led by the University of Maryland has exploited a
weakness in VEEV's genetic code, resulting in a far less deadly mutant
version of the virus when tested in laboratory mice. The new discovery
could enable the development of a vaccine and other drugs to combat
VEEV. The findings were published online in the Journal of Virology
Like many other dangerous viruses, VEEV has RNA as its genetic
material instead of DNA. Because a similar weakness exists in RNA
viruses that pose serious health risks to humans - such as HIV, Zika,
chikungunya and others - the discovery could advance the development of
treatments for these viruses as well.
"RNA viruses tend to cause acute infections," said Jonathan Dinman,
professor and Chair of the UMD Department of Cell Biology and Molecular
Genetics, who is the senior author on the research paper. "You either
fight them off quickly, like the common cold, or they overwhelm you,
Dinman and his colleagues exploited a mechanism known as programmed
ribosomal frameshifting (PRF), which allows RNA viruses to pack a larger
amount of genetic information into a relatively short sequence of RNA.
By prompting an infected cell to read the same sequence of RNA in two
different phases, PRF allows a virus to create two different proteins
instead of one.
The researchers created a mutant version of VEEV with a disrupted
PRF mechanism, which impaired the virus' ability to create a second
protein from a specific section of RNA. Tests in cultured cells did not
reveal a large difference in the rate of virus production. But when the
researchers tested the mutant virus in laboratory mice, they saw a
dramatic increase in the rate at which infected mice survived the
"With some simple mutations, we compromised VEEV's ability to be a
virulent virus," said Joe Kendra, a biological sciences graduate student
at UMD and the lead author of the study. "This result shows that PRF
might be a therapeutic target for other viruses. If we can confirm that
the mutant virus confers immunity, opening the door to a vaccine, that
will be very exciting."
In addition to a higher survival rate of mice infected with mutant
VEEV, the researchers also noted a lower incidence of the virus
accumulating in brain tissues. Dinman, Kendra and their co-authors
suspect that the missing protein in the mutant virus plays a role in the
virus' ability to cross the blood-brain barrier - an essential step to
cause brain swelling.
"It's interesting that the virus uses PRF to survive, but we can
also manipulate that mechanism to work against it," said study co-author
Yousuf Khan, an undergraduate biological sciences major and Goldwater
Scholar at UMD. "This is a new way to target viruses and make vaccines.
It opens up a lot of new research questions."
According to Dinman, the finding is particularly encouraging in
light of the challenge posed by climate change, as viral diseases begin
to extend their range north beyond the tropics.
"So many of these diseases are borne by mosquitoes. Chikungunya is
now established in the Caribbean, and Zika has been found in two
counties in Florida," Dinman said. "These viruses are on our doorstep.
But these results give us hope. Developing a vaccine takes a long time,
but with a concerted effort across government and academic labs, we have
a good chance."